title: Development of a glycoprotein D-expressing dominant-negative and replication-defective herpes simplex virus 2 (HSV-2) recombinant viral vaccine against HSV-2 infection in mice.
abstract: Using the T-REx (Invitrogen, California) gene switch technology and a dominant-negative mutant polypeptide of herpes simplex virus 1 (HSV-1)-origin binding protein UL9, we previously constructed a glycoprotein D-expressing replication-defective and dominant-negative HSV-1 recombinant viral vaccine, CJ9-gD, for protection against HSV infection and disease. It was demonstrated that CJ9-gD is avirulent following intracerebral inoculation in mice, cannot establish detectable latent infection following different routes of infection, and offers highly effective protective immunity against primary HSV-1 and HSV-2 infection and disease in mouse and guinea pig models of HSV infections. Given these favorable safety and immunological profiles of CJ9-gD, aiming to maximize levels of HSV-2 glycoprotein D (gD2) expression, we have constructed an ICP0 null mutant-based dominant-negative and replication-defective HSV-2 recombinant, CJ2-gD2, that contains 2 copies of the gD2 gene driven by the tetracycline operator (tetO)-bearing HSV-1 major immediate-early ICP4 promoter. CJ2-gD2 expresses gD2 as efficiently as wild-type HSV-2 infection and can lead to a 150-fold reduction in wild-type HSV-2 viral replication in cells coinfected with CJ2-gD2 and wild-type HSV-2 at the same multiplicity of infection. CJ2-gD2 is avirulent following intracerebral injection and cannot establish a detectable latent infection following subcutaneous (s.c.) immunization. CJ2-gD2 is a more effective vaccine than HSV-1 CJ9-gD and a non-gD2-expressing dominant-negative and replication-defective HSV-2 recombinant in protection against wild-type HSV-2 genital disease. Using recall response, we showed that immunization with CJ2-gD2 elicited strong HSV-2-specific memory CD4(+) and CD8(+) T-cell responses. Collectively, given the demonstrated preclinical immunogenicity and its unique safety profiles, CJ2-gD2 represents a new class of HSV-2 replication-defective recombinant viral vaccines in protection against HSV-2 genital infection and disease.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Natalie V
authors.initials: NV
authors.lastname: Akhrameyeva
authors.forename: Pengwei
authors.initials: P
authors.lastname: Zhang
authors.forename: Nao
authors.initials: N
authors.lastname: Sugiyama
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Behar
authors.forename: Feng
authors.initials: F
authors.lastname: Yao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006561:Herpes Simplex / Q000276:immunology / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D014759:Viral Envelope Proteins / Q000235:genetics*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D014759:Viral Envelope Proteins; D014765:Viral Vaccines; C040570:glycoprotein D-herpes simplex virus type 2